CDK9

protein-coding

cyclin dependent kinase 9, the group of Cyclin dependent kinases|P-TEFb complex subunits

Gene summary

The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS. [provided by RefSeq, Jul 2008]

Previous symbols:

CDC2L4

MANE transcript

NM_001261.4

Inheritance

AD, AR

ClinVar variants

P:1U:41B:33

Top phenotype

CDK9-related disorder

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr9:127,785,679-127,790,792

External References & Databases

Ensembl (ENSG00000136807)

Transcript & Mutation Effects

hg38 • Region Span ~5.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary breast carcinomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Ambry Genetics

CHARGE syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008965

Submitter: LiferaOmics

Genetic evidence – Published PMID: 26633546 – Families 1–5 – five unrelated probands. Five unrelated probands reported with homozygous CDK9 NM_001261.4:c.673C>T; p.(Arg225Cys) in a cohort of consanguineous families with dysmorphology/CHARGE-like features. Case-level (AR homozygous; non-LOF start = 0.1; missense; consanguinity—no deduction applied) = 5 × 0.1 = 0.5; Segregation = 0 (not explicitly quantified per family; conservative); Case-control = 0 Families 1–5 total = 0.5 PMID: 33640901 – Family 6 – one proband. One independent proband with compound heterozygous CDK9 variants (p.A288T / p.R303C) and CHARGE-like malformation syndrome with retinal dystrophy. Case-level (AR compound heterozygous; non-LOF; two missense variants evaluated independently) = 0.2; Segregation = 0; Case-control = 0 Family 6 total = 0.2 Published genetic evidence total = 0.7 / 12 Genetic evidence – Our cases Family 7 – one proband. Homozygous CDK9 c.673C>T; p.(Arg225Cys) in a consanguineous family with phenotype consistent with CHARGE-like syndrome. Case-level (AR homozygous; non-LOF start = 0.1; missense; no consanguinity deduction applied) = 0.1; Segregation = 0; Case-control = 0 Family 7 total = 0.1 Total genetic evidence (published AR + our cases) 0.7 (published) + 0.1 (our case) = 0.8 / 12 Experimental evidence – Published PMID: 33640901 – Functional alteration (engineered system; kinase assay). Disease-associated CDK9 variants (p.Arg225Cys, p.A288T, p.R303C) demonstrated reduced kinase activity compared to wild type, supporting a damaging effect on protein function. Functional alteration = 1.0 PMID: 33640901 – Model / biological plausibility. • CDK9 regulates morphogenesis in zebrafish (brain, heart, eye, vasculature) • Mouse loss-of-function: complete LoF is lethal; heterozygous LoF associated with structural abnormalities This supports biological relevance to multisystem developmental phenotypes. Model system / biological plausibility = 1.0 Experimental evidence total = 2.0 / 6 Overall score • Genetic evidence = 0.8 / 12 • Experimental evidence = 2.0 / 6 • Overall score = 2.8 / 18

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDK9 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 84

CDK9-related disorderTotal: 14

not providedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001261.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	32 clinvar		33
missense		1 clinvar	39 clinvar			40
nonsense				1 clinvar		1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	1	41	33	0	75

Highest pathogenic variant AF is 0.000028685172

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001261.4	RefSeq	NP_001252.1	7	MANE Select
ENST00000373264.5	Ensembl	ENSP00000362361.4	7	MANE Select
ENST00000421939.5	Ensembl	ENSP00000395872.1	3	Standard
ENST00001048895.1	Ensembl	ENSP00000718712.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cdk9	Danio rerio	Structure: hematopoietic multipotent progenitor cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

cdk9

Danio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional misregulation in cancer - Homo sapiens (human)
MicroRNAs in cardiomyocyte hypertrophy
IL-9 Signaling Pathway
Cardiac Hypertrophic Response
Initiation of transcription and translation elongation at the HIV-1 LTR

Biological Process

DNA repair
regulation of DNA repair
transcription by RNA polymerase II
transcription initiation from RNA polymerase II promoter
transcription elongation from RNA polymerase II promoter

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
transcription coactivator binding
DNA binding
chromatin binding
protein kinase activity

Cellular Component

cyclin-dependent protein kinase holoenzyme complex
nuclear chromatin
nucleus
nucleoplasm
chromosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373264
Coding exons: 7
Length: 5109
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125743
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.14	145	238	0.609	0.0000149	2450
Missense (PolyPhen)		56	78.518	0.71321		852
Synonymous	-2.27	126	97.5	1.29	0.00000633	713
Loss of Function	1.70	9	16.5	0.547	7.70e-7	189

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000064	0.000062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0.00041	0.00040	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single- stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. {ECO:0000269|PubMed:10393184, ECO:0000269|PubMed:10574912, ECO:0000269|PubMed:10757782, ECO:0000269|PubMed:10912001, ECO:0000269|PubMed:11112772, ECO:0000269|PubMed:11145967, ECO:0000269|PubMed:11575923, ECO:0000269|PubMed:11809800, ECO:0000269|PubMed:11884399, ECO:0000269|PubMed:12037670, ECO:0000269|PubMed:14701750, ECO:0000269|PubMed:15564463, ECO:0000269|PubMed:16109376, ECO:0000269|PubMed:16109377, ECO:0000269|PubMed:17956865, ECO:0000269|PubMed:18362169, ECO:0000269|PubMed:19575011, ECO:0000269|PubMed:19844166, ECO:0000269|PubMed:20081228, ECO:0000269|PubMed:20493174, ECO:0000269|PubMed:20930849, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21127351, ECO:0000269|PubMed:9857195}.;
Disease: DISEASE: Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy, and confers predisposition to heart failure.;

Recessive Scores

pRec: 0.359

Intolerance Scores

LoFtool: 0.579
RVIS EVS: -0.58
RVIS percentile EVS: 18.44

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium